Current therapy for severe hemorrhagic trauma patients consists of hemorrhage control and volume expansion. Depending on the severity of the hemorrhage and the time lag between injury and hemostasis, some patients with hemorrhagic shock may enter into irreversible circulatory collapse, despite resuscitation. We now understand that circulatory shock, through rheological and ischemic processes, induces hemodynamic, metabolic, and hyper-acute inflammatory responses that interact in a complex fashion and may lead to the development of refractory hypotension and irreversible shock. We have demonstrated that "real-time" monitoring of pH, oxygenation, and capnometry in skeletal muscle and other organs correlates with the severity of the hemorrhagic insult. However, these measurements have not been correlated directly with the inflammatory process, nor is the contribution of acute inflammation to irreversible shock well understood. In parallel, we have developed and calibrated a mathematical model that describes the mediators of acute inflammation in hemorrhagic shock. Though informed by circulating mediators, this model expresses the physiological derangement experienced by individual organs in terms of a global, currently theoretical, tissue dysfunction equation. We hypothesize that the magnitude of tissue dysfunction associated with circulatory collapse is a reflection of a global energetic failure and ensuing acute inflammation, which we can measure and model mathematically. Irreversible shock may result from severe exsanguination of short duration, or a more subdued, continuous hemorrhage, and/or delayed or inadequate resuscitation. We propose a systematic series of experiments in mice and swine to delineate irreversible shock. These experiments will be integrated within the mathematical framework previously developed. We propose the following two Specific Aims: 1) to characterize circulatory collapse in mice, and to augment a mathematical model of post-shock inflammation to include relevant neuroendocrine, cardiovascular and tissue metabolic elements; and 2) to validate the ability of several markers of tissue hypoperfusion to inform a mathematical model of post-shock inflammation in swine, and to provide specific outcome predictions. Within the scope of these Specific Aims, we will test the therapeutic efficacy of Ringer's Ethyl Pyruvate Solution (REPS), hypothesizing that the proven anti-inflammatory properties in moderate hemorrhagic shock will improve outcome in irreversible shock. These novel approaches to hemorrhagic shock may save lives on the battlefield by identifying high risk, high mortality victims and by aiding in assessing the severity or irreversibility of cell function in a multiple casualty scenario. On a more basic level, this research will advance the use of complex systems in biology. Our approach of mathematical modeling integrated with data in relevant animal models, and the associated data analysis, fitting, and statistics problems, will define new methodologies for systems biology research.